Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance.
Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance.
复制标题
尼达尼布和 Alpelisib 靶向肿瘤和基质细胞克服了膀胱癌的内在抵抗力。
DOI：
10.1158/1535-7163.mct-21-0667
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发表时间：
2023
影响因子：
5.7
通讯作者：
Real,FranciscoX
中科院分区：
文献类型：
--
作者：
Marqués,Miriam;Corral,Sonia;Sánchez-Díaz,María;DelPozo,Natalia;MartínezdeVillarreal,Jaime;Schweifer,Norbert;Zagorac,Ivana;Hilberg,Frank;Real,FranciscoX
膀胱癌是一种非常普遍的肿瘤，迫切需要开发新的治疗方法，特别是局部晚期和转移性疾病。尼达尼布是一种有效的抗纤维化血管激酶抑制剂，在局部晚期肌肉浸润性膀胱癌患者联合化疗中显示出临床疗效。尼达尼布抑制成纤维细胞生长因子受体（FGFRs），这是膀胱癌患者携带fgfr3 /2基因改变的有效靶点。在这里，我们旨在研究其作用机制，以了解治疗耐药，识别预测反应的标志物，并改进未来临床试验的设计。我们使用了一组基因特征良好的人类膀胱癌细胞，以鉴定在体外和体内、肿瘤和间质细胞水平上用尼达尼布治疗诱导的分子和转录组变化。我们发现膀胱癌细胞在体外表现出对尼达尼布治疗的内在耐药性，独立于其fgfr3状态。然而，尼达尼布对小鼠异种移植物具有较高的抗肿瘤活性。我们已经确定了PI3K激活是膀胱癌对尼达尼布的耐药机制，并证明了尼达尼布与PI3K抑制剂alpelisib的联合具有协同抗肿瘤活性。联合治疗与肿瘤和间质水平的细胞周期抑制以及对α-平滑肌肌动蛋白阳性肿瘤浸润细胞和肿瘤血管的有效非肿瘤细胞自主作用有关。尼达尼布联合PI3K抑制剂不仅逆转了膀胱癌对尼达尼布的耐药，而且增强了其抗血管生成作用。
Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboringFGFR3/2genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib,in vitroandin vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatmentin vitro, independently of theirFGFR3status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin—positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects.